Nuove terapie in ambito Nefrologico: Etelcalcetide (AMG-416)

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1 Nuove terapie in ambito Nefrologico: Etelcalcetide (AMG-416) Antonio Bellasi, MD, PhD U.O.C. Nefrologia & Dialisi ASST-Lariana, Ospedale S. Anna, Como, Italy

2 Improvement of mineral and bone metabolism markers is associated with better survival in haemodialysis patients: the COSMOS study Fernandez-Martin Nephrol Dial Transplant (2015) 0: 1 10

3 COSMOS: the dialysis scenario of CKD MBD in Europe Fernandez-Martin Nephrol Dial Transplant (2013) 28: Phosphate KDIGO 70,5 K/DOQI , ,8 41,4 20 2,8 7,2 26,7 29, ,5 12,7 6,5 0 Below target Within target Above target Below target Within target Above target Calcium KDIGO K/DOQI PTH ,1 31,2 36,5 29,1 34,4 12,7 Below target Within target Above target KDIGO K/DOQI

4 Structure and characteristics of AMG 416 compared to cinacalcet

5 Walter S, et al. J Pharmacol Exp Ther 2013;346: Mimpara (cinacalcet) prescribing information, Amgen. Goodman WG. Adv Ren Replace Ther. 2002;9: Goodman WG, et al. Kidney Int. 2008;74: Silver J, et al. Kidney Int. 2009;75: Moallem E, et al. J Biol Chem. 1998;273: Brown EM. Rev Endocr Metab Disord. 2000;1: Structure and Characteristics of AMG 416 Compared to Cinacalcet AMG 416 and Cinacalcet: Calcimimetic Agents With Similar Characteristics but Different Structures and Routes of Administration Ca ++ Parathyroid Gland Chief Cell Cartoon representation. Increased Intracellular Signaling CaSR AMG 416 Cinacalcet G Proteins Nucleus AMG 416 1,2,3 Cinacalcet 4,5 Calcimimetic Synthetic 8-amino acid peptide compound molecular weight = g/mol Interacts with the extracellular domain of CaSR to enhance signal transduction, thereby reducing PTH secretion Long-acting IV form Calcimimetic Small organic molecule; molecular weight = g/mol Interacts with membrane-spanning segments of CaSR and enhances signal transduction, thereby reducing PTH secretion Short-acting Oral form Regulation and Decreased Secretion of PTH IV = intravenous; CaSR = calcium-sensing receptor; PTH = parathyroid hormone.

6 Take home messages from Phase 1a Clinical Program Single IV doses of AMG 416, a long-acting selective peptide agonist of the CaSR, were generally safe and well tolerated in healthy male subjects. Dosing with AMG 416 resulted in dose-dependent reductions in ipth. AMG 416 mediated a dose-dependent reduction in plasma ica. AMG 416 was associated with a dose-dependent reduction in serum FGF23 but did not significantly reduce 1,25 vitamin D or calcitonin.

7 Etelcalcetide Clinical Program Etelcalcetide Clinical Program for SHPT in Patients With CKD on Dialysis Phase 3 Study (N = 508) R, DB, PC DB = double-blind; H2H = head-to-head; OLE = open-label extension PC = placebo-controlled; R = randomized Single-Arm OLE Study (N ~1120) Single-Arm Switch Study (N = 148) Phase 3 Study (N = 513) R, DB, PC Phase 2, Safety Extension Study (N = 30) Long-Term, Single-Arm OLE Study (n ~815) Head-to-Head Study Etelcalcetide vs Cinacalcet (N = 683) Martin KJ, et al. Poster Presented at the 2015 ASN Annual Meeting;November 3-8, 2015;San Diego, CA (# SA-PO1115).

8 Pivotal Phase 3 Studies ( and )

9 Pivotal Phase 3 Studies ( and ) Study Design Stratification factors: Serum ipth < 600 pg/ml pg/ml > 1000 pg/ml Cinacalcet use within 8 weeks before randomization Region North America Non North America IP initiation AMG SOC (n ~250 per study) Placebo + SOC (n ~250 per study) Screening phase Treatment phase Follow-up phase 8 weeks 26 weeks 30 days Phase 3, 26-week, multicenter, randomized, double-blind, placebo-controlled studies. All patients, regardless of treatment assignment, received SOC with calcium supplements, active vitamin D sterols, and phosphate binders (as prescribed by investigators). Study differences: Timing/frequency of acquisition of ECGs and laboratory tests including, but not limited to, chemistry and pharmacokinetics at day 1, and at weeks 5, 13, and 26 are obtained prior to and after dialysis for Study and prior to dialysis for Study ECG = electrocardiogram; IP = investigational product.

10 AMG 416 Phase 3, Placebo-Controlled Clinical Studies Study Population Key inclusion criteria Key exclusion criteria Adults 18 years receiving HD thrice a week for 3 months 1,2 Two consecutive PTH levels > 400 pg/ml and cca 8.3 mg/dl on separate days within 2 weeks before randomization 3 No substantial dose change of calcium supplements, phosphate binders, dialysate calcium, or active vitamin D for 4 weeks before screening 3 No participation in another study of an IP 1,2 Received cinacalcet within 4 weeks of study or during study 1,2 Parathyroidectomy within 3 months prior to dosing 1,2 Anticipated or scheduled kidney transplant during study period 1,2 Known sensitivity to any of the products or components during dosing Prior participation in a clinical trial of AMG 416 1,2 Unstable medical condition based on medical history, physical examination, and routine laboratory tests, or judged unstable in the investigator s opinion 1,2 History of any illness, which in the investigator s opinion, might confound the results of the study or pose additional risk 1,2 cca = corrected calcium; HD = hemodialysis; IP = investigational product; PTH = parathyroid hormone Elaborated from: 1. ClinicalTrials.gov. NCT Accessed May 20, ClinicalTrials.gov. NCT Accessed May 20, Cunningham J, et al. Late Breaking Presentation at the 52 nd ERA-EDTA Congress; May 29, 2015; London, UK. (Amgen Data on File).

11 AMG 416 Phase 3, Placebo-Controlled Clinical Studies Study Endpoints Primary endpoint Secondary endpoint The proportion of patients with > 30% reduction from baseline in mean PTH during the EAP (weeks 20-27) The proportion of patients with mean PTH 300 pg/ml Percent reductions in PTH, cca, cca x phosphate, and phosphate cca = corrected calcium; EAP = efficacy assessment phase; PTH = parathyroid hormone

12 Proportion of Patients With > 30% Mean PTH Reduction (%) AMG 416 Phase 3, Placebo-Controlled Clinical Studies Patients Randomized to AMG 416 Were More Likely to Achieve the Primary Efficacy Endpoint A higher proportion of patients treated with AMG 416 achieved > 30% reduction from baseline in mean PTH compared to placebo (74.7% vs 8.9%; P < 0.001) 1,2 PTH = parathyroid hormone % 8.9% Placebo AMG 416 (n = 514) (n = 509) Adapted from: 1. Cunningham J, et al. Presented at the 52 nd ERA-EDTA Congress; May 2015; London, UK. Abstract 15-LBA Cunningham J, et al. Late Breaking Presentation at the 52 nd ERA-EDTA Congress; May 29, 2015; London, UK. (Amgen Data on File).

13 AMG 416 Phase 3, Placebo-Controlled Clinical Studies Mean PTH Over Time Treatment with AMG 416 resulted in a greater reduction from baseline in mean PTH compared to placebo 1,2

14 AMG 416 Phase 3, Placebo-Controlled Clinical Studies Other CKD-MBD parameters

15 Percent of Patients Receiving Calcium Supplements/Calcium-containing Blinders Percent of Patients Receiving Active Vitamin D AMG 416 Phase 3, Placebo-Controlled Clinical Studies Percentage of Patients Receiving Calcium Supplements/Calcium- Containing Binders or Active Vitamin D Analogs About 7% vs 3% of patients experienced severe hypocalcemia (cca < 7.0 mg/dl) Use of Calcium Supplement/Calcium-containing Binder by Study Week Use of Active Vitamin D Analog by Study Week Placebo AMG Placebo AMG BL Study Week 60 BL Study Week Placebo n AMG 416 n Placebo n AMG 416 n BL = baseline Adapted from: Cunningham J, et al. Late Breaking Presentation at the 52 nd ERA-EDTA Congress; May 29, 2015; London, UK. (Amgen Data on File).

16 AMG 416 Phase 3, Placebo-Controlled Clinical Studies Safety Summary Placebo (n = 513) AMG 416 (n = 503) *Blood calcium decreased 10.1 % 63.8 % *Muscle spasms 6.6 % 11.5 % *Diarrhea 8.6 % 10.7 % *Nausea 6.2 % 10.7 % *Vomiting 5.1 % 8.9 % *Headache 6.0 % 7.6 % *Symptomatic hypocalcemia 0.2 % 7.0 % Hyperkalemia/increased potassium 3.1 % 4.4 % Death 2.9 % 2.2 % AEs occurred in 92% and 80% of AMG 416- and placebo-treated patients, respectively 1 The most common AEs in the AMG 416 group included nausea, vomiting, blood calcium decrease and diarrhea as were symptoms potentially related to hypocalcemia such as muscle spasms, headache, and paresthesias 1 Significant, but clinically silent, QT prolongation was observed in some AMG 416-treated patients, which may be related to changes in calcium 1 Hyperkalemia was reported more frequently in the AMG 416 group; detailed review of these events showed no consistent risk factors or associated events 1 Rates of death, adjudicated major nonfatal CV events and seizures were similar in both treatment groups 2 * Events occurring in 5% of AMG 416 patients, with 1% difference between groups; AE = adverse event Adapted from: 1. Cunningham J, et al. Late Breaking Presentation at the 52 nd ERA-EDTA Congress; May 29, 2015; London, UK. (Amgen Data on File). 2. Cunningham J, et al. Presented at the 52 nd ERA-EDTA Congress; May 2015; London, UK. Abstract 15-LBA-3558.

17 Head-to-Head Study (AMG 416 Versus Cinacalcet)

18 Head-to-Head Study (AMG 416 Versus Cinacalcet) Study Design Stratification factors: Serum PTH level: < 900 pg/ml 900 pg/ml Region North America Non North America TIW IV AMG daily oral placebo n ~300 Daily oral cinacalcet + TIW IV placebo n ~ day safety follow-up visit Screening phase Treatment phase Follow-up phase 8 weeks 26 weeks 30 days Day 1 (first dose) Dose titration (16 weeks) 26 weeks (last dose) Maintenance (10 weeks) Phase 3, multicenter, randomized, active-controlled, double-blind, double-dummy, dose-titration, 26-week study comparing AMG 416 and cinacalcet. All patients, regardless of treatment assignment, will receive SOC along with calcium supplements, nutritional vitamin D supplements, and phosphate binders. SOC = standard of care.

19 Head-to-Head Study: Etelcalcetide Vs Cinacalcet Key eligibility criteria Study Population Central laboratory screening predialysis serum PTH value > 500 pg/ml and serum albumin cca 8.3 mg/dl No cinacalcet use for 3 months Dialysate calcium concentration 2.5 meq/l for at least 4 weeks prior to screening Stable dose of vitamin D sterols for 4 weeks, calcium supplements for 2 weeks, and phosphate binders for 2 weeks prior to screening Study Endpoints Primary Endpoint Key Secondary Endpoints Achievement of a > 30% reduction from baseline in mean predialysis serum PTH level during the EAP (noninferiority) a Achievement of: > 50% reduction from baseline in mean predialysis serum PTH level during the EAP (superiority) b > 30% reduction from baseline in mean predialysis serum PTH level during the EAP (superiority) b Mean number of days of vomiting or nausea (PRO) per week in the first 8 weeks c EAP = efficacy assessment phase

20 Head-to-Head Study: Etelcalcetide Vs Cinacalcet Key eligibility criteria Study Population Central laboratory screening predialysis serum PTH value > 500 pg/ml and serum albumin cca 8.3 mg/dl No cinacalcet use for 3 months Dialysate calcium concentration 2.5 meq/l for at least 4 weeks prior to screening Stable dose of vitamin D sterols for 4 weeks, calcium supplements for 2 weeks, and phosphate binders for 2 weeks prior to screening Study Endpoints Primary Endpoint Key Secondary Endpoints Achievement of a > 30% reduction from baseline in mean predialysis serum PTH level during the EAP (noninferiority) a Achievement of: > 50% reduction from baseline in mean predialysis serum PTH level during the EAP (superiority) b > 30% reduction from baseline in mean predialysis serum PTH level during the EAP (superiority) b Mean number of days of vomiting or nausea (PRO) per week in the first 8 weeks c EAP = efficacy assessment phase

21 Head-to-Head Study: Etelcalcetide Vs Cinacalcet - Centers Enrollment from August 2013 to May End of Follow-up January 2015

22 Head-to-Head Study: Etelcalcetide Vs Cinacalcet - Centers Enrollment from August 2013 to May End of Follow-up January 2015

23 Head-to-Head Study: Etelcalcetide Vs Cinacalcet Etelcalcetide Was Noninferior to Cinacalcet in the Proportion of Patients With a > 30% Reduction in Serum PTH From Baseline during the EAP Proportion of Patients With > 30% Serum PTH Reduction From Baseline (%) ,7 EAP was defined as weeks EAP = efficacy assessment phase; PTH = parathyroid hormone. P for non inferiority < ,2 Cinacalcet Etelcalcetide (n = 343) (n = 340) Etelcalcetide and Cinacalcet Dosing: The median average weekly etelcalcetide dose during the efficacy assessment phase was 15.0 mg (interquartile range [IQR], mg) and the median average daily cinacalcet dose was 51.4mg (IQR, mg).

24 Head-to-Head Study: Etelcalcetide Vs Cinacalcet

25 Head-to-Head Study: Etelcalcetide Vs Cinacalcet Etelcalcetide Was Superior to Cinacalcet in the Proportion of Patients With a > 50% Reduction From Baseline in Mean Serum PTH During the EAP Proportion of Patients With > 50% Mean PTH Reduction From Baseline (%) % P = % Cinacalcet Etelcalcetide (n = 138) (n = 178) EAP was defined as weeks EAP = efficacy assessment phase; PTH = parathyroid hormone.

26 Head-to-Head Study: Etelcalcetide Vs Cinacalcet

27 Percent Change Head-to-Head Study: Etelcalcetide Vs Cinacalcet Changes in Biomarkers: FGF-23, BSAP, and CTX (Median Percent Change From Baseline to Week 27) Etelcalcetide was associated with greater reductions in FGF-23, BSAP, and CTX from baseline to week 27 compared with cinacalcet ( 76, 25) FGF-23 BSAP CTX 68 ( 87, 26) Cinacalcet Etelcalcetide ( 40, 20) ( 42, 13) 29 ( 50, 2) 36 ( 57, 6) BSAP = bone-specific alkaline phosphatase; CTX = type 1 collagen C-telopeptide; FGF = fibroblast growth factor; SE = standard error.

28 Head-to-Head Study: Etelcalcetide Vs Cinacalcet Safety Summary: Most Common AEs Cinacalcet (n = 341) n (%) Etelcalcetide (n = 338) n (%) All TEAEs a 307 (90.0) 314 (92.9) Serious AEs 93 (27.3) 85 (25.1) Leading to discontinuation of IP 16 (4.7) 19 (5.6) Patient incidence of TEAEs b Asymptomatic blood calcium decreased 204 (59.8) 233 (68.9) Nausea 77 (22.6) 62 (18.3) Vomiting 47 (13.8) 45 (13.3) Hypotension 10 (2.9) 23 (6.8) Headache 24 (7.0) 22 (6.5) Muscle spasms 20 (5.9) 22 (6.5) Diarrhea 35 (10.3) 21 (6.2) Hypertension 23 (6.7) 21 (6.2) Anemia 15 (4.4) 17 (5.0) Symptomatic hypocalcemia 8 (2.3) 17 (5.0) Pain in extremity 14 (4.1) 17 (5.0) Bronchitis 17 (5.0) 5 (1.5) AEs and serious AEs were comparable between the treatment groups The most frequently reported events that led to the discontinuation of IP (etelcalcetide, cinacalcet) were vomiting (0.9%, 0.3%) and nausea (0.6%, 0.9%) a This does not include one patient that had a fatal event 80 days after the last dose of IP, which is outside the protocol-defined period of 30 days after the last dose of IP for TEAEs; b Occurring in 5% of patients in either treatment group by preferred term. AE = adverse event; IP = investigational product; TEAE = treatment-emergent adverse event.

29 Head-to-Head Study: Etelcalcetide Vs Cinacalcet Safety Summary: Fatal AEs Fatal AEs were reported in 9 (3%) and 6 (2%) patients in the etelcalcetide and cinacalcet groups, respectively; none were considered to be related to IP A numerical imbalance for AEs related to cardiac failure occurred in the etelcalcetide group (3.0%) compared with the cinacalcet group (0.6%) Events of cardiac failure were serious in 5 patients (including 3 fatal AEs) and 1 patient (no fatal AEs) in the etelcalcetide and cinacalcet groups, respectively None of the fatal or serious AEs of cardiac failure were reported in the setting of hypocalcemia; 2 nonserious events in the etelcalcetide group were associated with low cca values of 8.0 mg/dl and 8.1 mg/dl None of these events were deemed to be related to the IP AE = adverse event; cca = corrected calcium; IP = investigational product.

30 Mean (SE) Head-to-Head Study: Etelcalcetide Vs Cinacalcet Mean Number of Days of Vomiting or Nausea For the First 8 Weeks a 0,5 0,4 P = ,4 0,3 0,3 0,2 0,1 0 Cinacalcet Etelcalcetide PRO = patient reported outcome; SE = standard error. a Prespecified secondary endpoint. Information about nausea and vomiting was collected using a PRO instrument.

31 S&C CKD-MBD, including SHPT, is an unmet medical need associated with poor quality of life as well as short life expectancy Newer compounds under clinical development should also increase compliance and treatment adherence Several newer compounds are anticipated to enrich the CKD-MBD therapeutic armamentarium and may potentially overcome the limitations of current agents. However, the greatest challenge still remains understanding how to individualize and optimize care according to baseline risks and the pathophysiologic process that drives abnormalities in mineral metabolism. Patient selection and identification of the prevalent pathophysiologic mechanism(s) are probably the key factors to improving outcome in patients with CKD-MBD.

32 Etelcalcetide Clinical Program Etelcalcetide Clinical Program for SHPT in Patients With CKD on Dialysis Phase 3 Study (N = 508) R, DB, PC DB = double-blind; H2H = head-to-head; OLE = open-label extension PC = placebo-controlled; R = randomized Single-Arm OLE Study (N ~1120) Single-Arm Switch Study (N = 148) Phase 3 Study (N = 513) R, DB, PC Phase 2, Safety Extension Study (N = 30) Long-Term, Single-Arm OLE Study (n ~815) Head-to-Head Study Etelcalcetide vs Cinacalcet (N = 683) Martin KJ, et al. Poster Presented at the 2015 ASN Annual Meeting;November 3-8, 2015;San Diego, CA (# SA-PO1115).

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